Epidemiological analysis of cocaine-related deaths in metropolitan Miami, Florida (1978 - 1990) has revealed a number of important findings regarding the temporal distribution of fatal cocaine overdoses and associated risk factors. The epidemiological findings indicate that 6 to 11 % of the cases had significant underlying coronary artery disease or ventricular hypertrophy, suggesting that these cardiovascular risk factors may explain only a small portion of the cocaine overdose deaths. Acute toxicity to high doses of cocaine is associated with seizures. However, we have confirmed that the percentage of cocaine-related deaths with seizures has continued to decline during the epidemic. This pattern is consistent with our toxicology findings, which demonstrate a decline in the median plasma concentrations of cocaine associated with sudden death. While polydrug abuse of cocaine and heroin or other opiates accounts for less than 6% per year of the overdose deaths, analysis of the annual frequency of ethanol detections shows that many subjects had combined cocaine with alcohol prior to death. This observation led our group to the identification of cocaethylene, a neuroactive metabolite of cocaine formed by liver enzymes in the presence of ethanol, as a possible risk factor for cocaine-related sudden death. In postmortem drug screens, we found cocaethylene in blood, liver and brain in concentrations equal to a sometimes exceeding those of the cocaine. One of the most serious psychiatric sequelae of cocaine abuse is excited delirium, which is associated with hyperthermia and sudden death. The annual incidence of excited delirium and sudden death cases in Miami parallels the epidemic curve for cocaine fatalities. Taken together, these observations suggest that different mechanisms may contribute to the potentially lethal neurologic, respiratory and cardiovascular effects of cocaine in decedents with comparatively low concentrations of blood cocaine as compared to high dose cocaine toxicity. Our hypothesis is that cocaine abuse results in abnormal activity in cortical limbic and brainstem centers which control cardiac function. Abnormal neurochemical transmission in these pathways may, in addition to the direct cardiotoxic effects of cocaine, lead to the pathogenesis of cocaine-related sudden death. This proposal request support to continue our ongoing studies aimed at characterizing neuroreceptor and neurotransporter regulation in the human brain postmortem from cocaine overdose deaths. The proposed studies in the human brain may pinpoint the neurotransmitter systems regulating cocaine's convulsant, respiratory and cardiovascular effects, suggest differences in neural recognition sites that mediate tolerance and sensitization, and provide a basis for pharmacotherapeutic interventions to treat cocaine toxicity.